rs758871283
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_138694.4(PKHD1):c.12200C>T(p.Pro4067Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P4067P) has been classified as Likely benign.
Frequency
Consequence
NM_138694.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.12200C>T | p.Pro4067Leu | missense_variant | 67/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.12200C>T | p.Pro4067Leu | missense_variant | 67/67 | 1 | NM_138694.4 | P2 | |
ENST00000589278.6 | n.811-3254G>A | intron_variant, non_coding_transcript_variant | 5 | ||||||
ENST00000454361.1 | n.81-3249G>A | intron_variant, non_coding_transcript_variant | 3 | ||||||
ENST00000650088.1 | n.222-3249G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152242Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251146Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135732
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461818Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14AN XY: 727224
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152360Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74512
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4067 of the PKHD1 protein (p.Pro4067Leu). This variant is present in population databases (rs758871283, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of PKHD1-related conditions (PMID: 16523049). ClinVar contains an entry for this variant (Variation ID: 550648). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PKHD1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 14, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 01, 2019 | Identified prenatally in a patient with a clinical diagnosis of autosomal recessive polycystic kidney disease, including anhydramnios and enlarged kidneys, in published literature (Adeva et al., 2006); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16523049) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at